N-Acetylcysteine Postsynaptic Effect Limits Efficacy

Despite promising results in animal studies, clinical trials of N-acetylcysteine to prevent relapse to drug abuse have demonstrated only moderate efficacy. New work by NIDA-funded scientists suggests a reason why, and points the way toward a more effective application of the strategy underlying the medication’s use.

Dr. Peter Kalivas and colleagues at the Medical University of South Carolina, in Charleston, identified N-acetylcysteine as a potential aid to substance abuse treatment because of its effect on the neurotransmitter glutamate (“Medications That Normalize Brain Glutamate Reduce Drug-Seeking in Rats”). The group’s research has shown that chronic drug abuse depletes extracellular glutamate in the reward system, and that this promotes two main features of addiction:

Compulsive drug-taking in response to drug-associated cues

Inability to change drug-taking behavior despite adverse effects

N-Acetylcysteine counters the problem by pushing glutamate stored in glial cells out into the extracellular space.

The team’s latest experiments reveal what happens when N-acetylcysteine raises extracellular glutamate in the critically important nucleus accumbens region of the reward system. At lower doses of the medication, the released glutamate stimulates presynaptic receptors (mGluR2/3) on neurons; at higher doses, more glutamate is released and an additional, postsynaptic receptor (mGluR5) is also stimulated.

The presynaptic stimulation dampens neuronal activity in the nucleus accumbens and, in rats, reduces the tendency to respond to cocaine-associated cues. The postsynaptic stimulation has opposite effects: it intensifies neuronal activity and partly offsets the positive effect on animals’ responses to drug cues.

The researchers propose that a medication or combination that both increases nonsynaptic extracellular glutamate to stimulate mGluR2/3 and inhibits mGluR5 may reduce the risk of relapse more effectively than N-acetylcysteine alone.